The present invention relates to the field of chemistry and more particularly to that of therapeutic chemistry.
More precisely, the subject of the present invention is new 2,4-thiazolidinedione derivatives, namely 5-phenoxyalkyl-2,4-thiazolidinediones, processes for producing them, their use and antidiabetic agents and in the treatment of the metabolic syndrome of insulin resistance, and the pharmaceutical compositions containing them.
Numerous 2,4-thiazolidinedione derivatives have already been described as antidiabetic agents (Takeda, Patent EP 193 256, Sankyo Patent EP 207 581).
The compounds previously described were mainly thiazolidinediones substituted at the 5 position by a benzyl radical, that is to say compounds having an alkylene chain containing only one carbon atom between the thiazolidine ring and an aryl group.
The structure of these compounds comprised in general variations on the substituent carried by the aryl ring of the benzyl radical.
Compounds possessing the structures previously described and exhibiting notable hypoglycaemic and hypotriglyceridaemic activities had as linkage at the 5 position the group Rxe2x80x94Oxe2x80x94Arxe2x80x94CH2xe2x80x94.
These variations affected exclusively the R substituent carried by the oxygen at the para position of the phenyl.
Some of these compounds, beside their pharmacological properties, manifest hepatotoxicity phenomena (Takashi Sohda, Chem. Pharm. Bull 30 (1982) 3580).
It is known that, in non-insulin-dependent diabetes, a decrease in the efficacy of insulin leads to hyperglycaemia.
The decrease in the xe2x80x9cactivityxe2x80x9d of insulin is linked, on the one hand, to a pancreatic defect in the insulin response to glucose and, on the other hand, to a hepatic and peripheral (musclesxe2x80x94adipose tissues) insulin resistance.
Some current antidiabetic therapies stimulate mainly insulin secretion, without enhancing insulin resistance, and have as major defect, in the long term, the worsening of the diabetes by depletion of the xcex2-pancreatic cells.
Other antihyperglycaemics such as Metformin and the compounds having the 2,4-thiazolidinedione structure enhance the sensitivity to insulin.
These thiazolidinediones reduce glycemia without stimulating the secretion of insulin and prove more active in insulin resistance with hyperinsulinism.
The compounds of the present invention are new and differ from other 2,4-thiazolidinedione derivatives in properties which the compounds of the prior art did not possess: absence of effect on the secretion of insulin, action on insulin resistance, absence of hepato toxic effect, activity in diabetics in the case of diabetes without hyperinsulinism.
The subject of the present invention is specifically the new 5-phenoxyalkyl-2,4-thiazolidinediones corresponding to the general formula I: 
in which
A represents a linear or branched alkylene group comprising from 2 to 16 carbon atoms
D represents a homo- or heterocarbon mono-, di- or tricyclic aromatic structure which may include one or more heteroatoms
X represents a substituent of the aromatic structure, chosen from hydrogen, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an alkoxyalkyl group in which the alkoxy and alkyl groups are defined as above, an aryl group defined as an aromatic cyclic structure comprising one or two rings optionally including one or two heteroatoms in the ring such as for example a phenyl or an xcex1- or xcex2-naphthyl, an aralkyl group in which the alkyl group is defined as above and the aryl group is defined as above and optionally comprises one or more substituents, an aralkylaryl group whose aralkyl and aryl fractions are defined as above, a halogen, a trifluoromethyl, a cyano, a hydroxyl, a nitro, an amino, a carboxyl, an alkoxycarbonyl, a carboxamide, a sulfonyl, a sulfone, a sulfonamide, a sulfamoyl, an alkylsulfonylamino, an acylamino, a trifluoromethoxy
n is an integer ranging from 1 to 3 with the proviso that if A represents the butyl radical, 
xe2x80x83does not represent the 4-chlorophenyl group.
In the preceding text, among the aromatic radicals D, there may be mentioned as homocarbon structure the phenyl, xcex1-naphthyl, xcex2-naphthyl or fluorenyl radical.
Among the heterocyclic aromatic radicals, there may be mentioned pyridyl, the quinolyl ring or carbazolyl.
As regards the invention, an alkyl group is defined as having from 1 to 6 carbon atoms and especially a methyl, ethyl, propyl, isopropy, butyl, isobutyl, tert-butyl or pentyl radical and the like, an alkoxy group is defined as having from 1 to 6 carbon atoms and especially a methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy radical and the like, a halogen group is defined as being fluorine, chlorine, bromine or iodine.
The alkylene chain A is a linear or branched hydrocarbon chain having from 2 to 16 carbon atoms, which is saturated or has one or more ethylene bonds, optionally substituted with a hydroxyl radical or with a phenyl radical. An example of such a chain will be an ethylene or propylene radical.
The present invention also relates to tautomeric forms of the compounds of general formula I, to the enantiomers, diastereoisomers and epimers of these compounds, as well as their solvates.
It can be envisaged that the ketone functions carried by the thiazolidine ring may become enolized and give rise to monoenols.
The thiazolidinedione derivatives of general formula I which possess an acidic proton on the nitrogen of the thiazolidinedione ring may, in this case, be salified and exist in the form of basic salts.
Examples of basic salts of the compounds of general formula I include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth and the like). The amine salts which are not pharmacologically acceptable may serve as means for identification, purification or resolution.
Among the compounds of general formula I according to the invention, there may be mentioned more particularly, as compounds currently preferred:
5-[3-(4-fluorophenoxy)propyl]-2,4-thiazolidinedione
5-(2-phenoxyethyl)-2,4-thiazolidinedione
5-[2-(4-fluorophenoxy)ethyl]-2,4-thiazolidinedione
5-{[1-hydroxy-2-(4-fluorophenoxy)]ethyl}-2,4-thiazolidinedione
5-{[2-hydroxy-3-(4-fluorophenoxy)]propyl}-2,4-thiazolidinedione
5-[1-methyl-2-phenoxyethyl]-2,4-thiazolidinedione
5-[2-(4-cyanophenoxy)ethyl]-2,4-thiazolidinedione
5-[2-(2-fluorophenoxy)ethyl]-2,4-thiazolidinedione
5-[2-(2-naphthyloxy)ethyl]-2,4-thiazolidinedione
and their pharmacologically acceptable salts.
The invention also relates to the processes for producing the 5-phenoxyalkyl-2,4-thiazolidinedione of general formula I.
A process of synthesis according to the invention, (route A), is a malonic synthesis, which consists in that a compound of formula II: 
in which X, D and n are defined as above,
is subjected to the action of a dihaloalkyl of formula III: 
in which
Hal represents a chlorine or bromine atom,
A is an alkylene radical defined as above,
in the presence of a basic agent, to form a compound of general formula IV: 
in which X, D, n and A are defined as above,
which is subjected to the action of a dialkyl malonate of formula V: 
in which R1 and Rxe2x80x21 are alkyl radicals,
in the presence of an alkali metal alcoholate, to form a compound of general formula VI: 
in which X, D, n, A, R1 and Rxe2x80x21 are defined as above,
which is subjected to halogenation by the action of a halogenating agent to form the compound of general formula VII: 
in which
Hal represents a chlorine or bromine atom,
X, D, n, A, R1 and Rxe2x80x21 are defined as above.
The malonic compound VI may be halogenated with an N-haloamide or an N-haloimide after formation of the anion, as for example by the action of sodium hydride in tetrahydrofuran.
The dialkyl diester of general formula VII is decarboxylated and saponified by heating in an acidic mixture consisting especially of hydrochloric acid and acetic acid to give the xcex1-haloacid of general formula VIII: 
in which Hal, X, D, n and A are defined as above,
which is reacted with thiourea to form a 2-imino-4-thiazolidinone of general formula IX: 
in which the X, D, n and A groups are defined as above,
which, without being necessarily isolated, is hydrolysed to a 2,4-thiazolidinedione of general formula I by adding an acidic mixture such as hydrochloric acid.
This hydrolysate is preferably carried out by heating under reflux.
In this process, the basic agent used to form the compound of general formula IV is preferably an alkali metal hydroxide and especially sodium hydroxide. Likewise, the haloamide may be N-chloroacetamide, N-bromoacetamide or N-bromobenzamide and the haloimide may be N-chlorosuccinimide or N-chlorophthalimide.
Another process of synthesis by the malonic route (route B) consists in subjecting a compound of formula X: 
in which
R represents an alkyl group,
X, D, n and A are as defined above,
to halogenation to form the xcex1-halogenated ester of general formula XI: 
in which
Hal represents a chlorine or bromine atom,
X, D, n and A are as defined above,
and then in reacting the latter with thiourea in the presence of a buffering agent such as sodium acetate to form the 2-imino-4-thiazolidinone of formula IX: 
in which X, D, n and A are as defined above,
which is hydrolysed by heating under reflux in hydrochloric acid, to form the thiazolidinedione of general formula I: 
in which
D represents a homo- or heterocarbon, mono-, di- or tricyclic aromatic structure which may include one or more heteroatoms,
X represents a substituent of the aromatic structure and is defined as above,
A represents a linear or branched alkylene group comprising from 2 to 16 carbon atoms.
Another process of synthesis, according to the invention (route C), consists in that a halogenated compound of formula IV: 
in which
Hal represents a chlorine or bromine atom,
X, D, n and A are defined as above,
is subjected to the action of the 2,4-thiazolidinedione dianion obtained by the action of an alkali metal derivative such as butyllithium on 2,4-thiazolidinedione to form a compound of general formula I.
In another process according to the invention (route D), the synthesis starts with an aryloxyalkyl aldehyde and consists in subjecting the aldehyde compound of formula XII: 
in which
B represents a linear or branched alkylene group, comprising from 1 to 15 carbon atoms
X, D and n are as defined above,
to the action of the 2,4-thiazolidinedione dianon obtained by the action of an alkali metal derivative on 2,4-thiazolidinedione,
to form a compound of general formula XIII: 
in which B, X, D and n are as defined above.
This compound is then converted to a dehydroxylated compound of formula I, by dehydration and then selective hydrogenation, or alternatively by reduction of the alcohol function to a saturated derivative.
The invention also relates to another process for preparing the compounds of general formula I (route E), in which an oxirane of formula XIV: 
in which
Bxe2x80x2 represents a linear or branched alkylene group comprising from 1 to 14 carbon atoms,
X, D and n are defined as above,
formed by reaction of an epihalohydrin on an aromatic derivative with [sic] the 2,4-thiazolidonedione dianion obtained by the action of a strong base such as butyllithium to form the compound of general formula XV: 
in which X, D, n and Bxe2x80x2 are defined as above.
The compound of formula XV is then converted to a dehydroxylated compound of general formula I by dehydration and hydrogenation.
Another process for producing the compounds of general formula I (route F) consists, starting with a ketone, in subjecting the said ketone of general formula XVI: 
in which
Rxe2x80x2 represents a linear or branched alkyl group, or an aryl or aralkyl group, substituted or not,
X, D, n and B are defined as above,
to the action of 2,4-thiazolidinedione in the presence of an organic base to form, after dehydration of the intermediate carbinol in an acidic medium, the compound of general formula XVII: 
in which X, D, n, B and Rxe2x80x2 are defined as above,
and then in reducing the double bond by hydrogenation in the presence of a catalyst, to form the compound of general formula I, in which the alkylene chain is a branched chain: 
X, D, n, B and Rxe2x80x2 are defined as above.
The catalytic hydrogenation of the compound XVII is carried out preferably in the presence of a metal of the platinum family on an inert support such as, for example, palladized charcoal, platinized charcoal or palladium on calcium carbonate.
To summarize, in the processes of synthesis C, D, E and F, the compounds of general formula I are obtained by the action of various electrophilic agents as described below, in a non-limiting manner on the 2,4-thiazolidinedione dianion, preferably at low temperature.
This dianion may be obtained by the action of a strong base such as lithium diethylamide, lithium amide, lithium diisopropylamide, n-BuLi, on 2,4-thiazolidinedione. 
D is defined as above,
X represents the substituent of the aromatic structure and is defined as above,
B represents a linear or branched alkylene group comprising from 1 to 15 carbon atoms,
Bxe2x80x2 represents a linear or branched alkylene group comprising from 1 to 14 carbon atoms,
Y represents a bromine or chlorine atom or a methylsulfonyloxy or p-toluenesulfonyloxy radical,
Rxe2x80x2 represents a linear or branched alkyl group, or alternatively Rxe2x80x2 represents an aryl or aralkyl group, substituted or not,
X1 represents a hydrogen or a linear or branched alkyl group,
or alternatively X1 represents an aryl or aralkyl group, substituted or not,
X2 represents a hydrogen or a linear or branched alkyl group,
or alternatively X2 represents an aryl or aralkyl group, substituted or not.
The invention also comprises, as new products, the intermediate compounds formed during the various processes of synthesis and especially the compounds of general formula: VII, VIII, IX, XIII, XV and XVII.
The compounds according to the invention manifest very valuable pharmacological properties and, as a result, find use in therapy.
The compounds of the invention differ from the other 2,4-thiazolidinedione derivatives in the intensity of their antidiabetic activity in models of diabetes without hyperinsulinism where the prior art compounds, such as for example troglitazone, prove to be little active.
Thus, the compounds of the invention can be used in the treatment of non-insulinopenic diabetic states, making it possible to obtain a better control of glycemia by having a reduced circulating insulin level.
The prevention of this relative hyperinsulinism, associated with an improvement of dyslipidaemias and an antioxidant activity, may contribute to a reduction in the micro- and macroangiopathic risks.
The compounds of the invention can be used in the treatment of the metabolic syndrome of insulin resistance involving a beneficial therapeutic effect on non-insulin-dependent diabetes, hypoinsulinism, hypertension and dyslipidaemiasxe2x80x94but also in non-insulin-dependent diabetes with hyperinsulinism.
The compounds find, furthermore, use in the treatment of hypertension in insulin resistant subjects, associated or otherwise with other metabolic abnormalities.
The diuretic activity and the reduction in the Ca2+ capture observed on rat aorta can cause an antihypertensive activity for some of the compounds of general formula I.
Some of the compounds possess, in addition, antiradical activities towards the hydroxyl and superoxide anion, demonstrated with the aid of a so-called cellular investigation model.
For these purposes, the compounds according to the invention are used in the form of pharmaceutical compositions which contain, as active ingredient, at least one compound of general formula I, in combination or mixed with a pharmaceutically acceptable non-toxic inert excipient or vehicle.
The pharmaceutical compositions according to the invention are intended for administration by the parenteral, digestive, rectal, permucosal or percutaneous route.
They will therefore be presented in the form of injectable solutions or suspensions or multi-dose vials, in the form of plain or coated tablets, sugar-coated tablets, capsules, gelatin capsules, pills, cachets, powders, suppositories or rectal capsules, solutions or suspensions, for percutaneous use in a polar solvent, or for permucosal use.
Suitable excipients are cellulose derivatives or microcrystalline cellulose, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches or lactose for the solid forms.
For rectal use, cocoa butter or polyethyleneglycol stearates are the preferred excipients.
For parenteral use, water, aqueous solutions, physiological saline, isotonic solutions are the vehicles most conveniently used.
The dosage may vary within wide limits according to the therapeutic indication and the route of administration, as well as the age and weight of the subject.
As a general rule, the unit dosage can range from 1 to 200 mg per dose and the daily dosage can range from 2 to 500 mg.